Men's Health (BPH, ED) Flashcards
BPH overview
Progressive condition
- Lower Urinary Tract Symptoms (LUTS)
- -ve impact on QoL
*characterised by NON-MALIGNANT growth of some components of the prostate eg. transitional zone
Prostate physiology:
- Epithelial (glandular) tissue -> ANDROGENS stimulate growth
- Stromal (smooth muscle) tissue -> innervated by alpha1 adrenergic receptors
*testosterone converted to dihydrotestosterone (DHT) by enzyme 5alpha-reductase IN PROSTATE
- DHT needed for NORMAL GROWTH/ ENLARGEMENT of prostate
Pathophysiology of BPH (*long term effects) + signs & symptoms
*likely age & hormonal factors
- Static component: Hormonal factors
- testosterone -> DHT
- ENLARGEMENT of prostate tissue - Dynamic component
- INCREASED smooth muscle tissue & AGONISM of alpha1 receptors
- NARROWING of urethra outlet
overall => URETHRAL OBSTRUCTION/ signs & symptoms
*early phase: bladder muscle able to force urine through urethra by CONTRACTING MORE FORCEFULLY
OVER TIME: bladder muscle gradually becomes THICKER (hypertrophy) to overcome obstruction
- Once detrusor muscle has achieved HIGHEST state of hypertrophy -> muscle DECOMPENSATES -> muscle becomes IRRITABLE &/ OVERLY SENSITIVE
-> CONTRACTS ABNORMALLY in response to SMALL amounts of urine in bladder -> urinary frequency
Signs & symptoms
*MANY PATIENTS REMAIN ASYMPTOMATIC (only 1/3 of pts >65y/o show s/sx)
- LOWER URINARY TRACT SYMPTOMS: weak stream, frequency, nocturia, intermittent stream, incomplete emptying, straining, urgency
*not specific to BPH, other causes: UTI, prostate/bladder cancer, DM
- [Early in disease] OBSTRUCTIVE/VOIDING symptoms
> Hesitancy
> Weak stream
> Sensation of incomplete emptying
> Dribbling
> Straining
> Intermittent flow
- [after several years of UNTREATED BPH] IRRITATIVE/ STORAGE symptoms
> Dysuria
> Frequency
> Nocturia
> Urgency
> Urinary incontinence (UI)
ED overview (definition, incidence), physiology of erection/ detumescence
PERSISTENT (at least 6 months) inability to achieve/ maintain an erection of sufficient duration & firmness to complete satisfactory intercourse
Incidence:
- Low in men <40y/o, INCREASING prevalence with increasing age
- ~50% of men >40y/o experience ED
*Physiology of erection
Flaccid state (penis): blood inflow balanced with blood outflow
Erection: arterial flow into penis INCREASES, venous outflow DECREASES
- INCREASED INFLOW: Smooth muscle RELAXES -> Corpora Cavernosa fills up with blood
*ACTIVATION of PARASYMPATHETIC system - Acetylcholine (ACh)
> ACh increases creation of NO -> increases activity of guanylate cyclase -> INCREASES cyclic cGMP
> ACh & PROSTAGLANDIN E -> increases adenyl cyclas -> increases cAMP
OVERALL => SMOOTH MUSCLE RELAXATION & VASODILATION => INCREASED blood INFLOW - DECREASED OUTFLOW: swelling causes compression of venules against tunica albuginea
*REQUIRES FUNCTIONAL HORMONAL SYSTEM: Testosterone (encourages libido)
- Usual normal serum conc of 300-1,000ng/DL( 10,4- 38.2nmol/L)
- to be assessed in the PERSPECTIVE of patient symptoms (low levels of testosterone =/= ED)
*Physiology of Detumescence
1) Deactivating of PARASYMPATHETIC system
> cGMP DEACTIVATED by PHOSPHODIESTERASE 5 (PDE-5) -> vasodilation STOPPED
*PDE-5 predominant enzyme in penis
2) Activated sympathetic system
> smooth muscle contraction INDUCED via alpha2 adrenergic receptors of arterioles -> REDUCTION of blood flow
*serotonin: postulated to have inhibitory effects on sexual arousal
Etiology of ED
Organic ED
> VASCULAR: arteriosclerosis // Peripheral vascular disease (PVD) // HTN // Diabetes
> HORMONAL: HYPOgonadism // HYPERprolactinemia (prolactin suppresses testosterone production)
> NERVOUS: [central] spinal cord trauma/ disorders, Stroke, CNS tumors // [peripheral] Diabetes, neuropathy, urethral surgery
> MEDICATION INDUCED: BP meds eg. BB, thiazides (decrease penile blood flow), Anticholinergics (decrease ACh activity), Dopamine antagonists (dopamine related to sexual arousal/ stimulation), SSRIs (increased serotonin in brain/ decreased testosterone), BPH meds (5ARI) (decreased testosterone), CNS depressants (suppresses perception of psychic stimulus)
*alternatives below
Psychogenic ED
*Psychological (due to thoughts/ feelings), rather than physical physiology
> Malaise
> Loss of attraction
> Stress
> Performance anxiety
> Mental disorders
> Sedation
Mixed ED
*combination of BOTH organic & psychogenic ED
Others *social environment
> Social habits: smoking, excessive ethanol intake, illicit drug use
> Obesity
*Alternative for med-induced organic ED:
BP meds: ACEi, ARBs, Loop diuretics, Nevibolol (mixed nonselective/selective BB)
Anticholinergics: Bupropion, trazodone, 2nd gen AH, atypical antipsychotics (2nd gen)
Dopamine antagonists: PPIs, erythromycin
SSRIs: Bupropion, trazodone
BPH meds: [alpha 1 adrenergic antagonists] terazosin, alfuzosin etc
CNS depressants: anticonvulsants (valproic acid/ gabapentin)
Assessment of BPH
Digital rectal exam (DRE)
Ultrasonography
Max Urinary Flow Rate (Qmax)
Postvoid Residual (PVR): <100ml normal, >200ml INADEQUATE EMPTYING
Prostate Specific Antigen *may be elevated in BPH & +vely correlated with PROSTATE VOLUME
-> can help predict progression of BPH (>1.5ng/mL)
-> HIGHER risk for prostate cancer
*controversial - not clear cut
International Prostate Symptom Score (IPSS)
- 0-7 mild
- 8-19 moderate
- 20-35 SEVERE
*quantitatively measures LUTS
* QoL score: >/=3 -> AFFECTING DAILY LIFE
*MEDICATION HISTORY:
- Anticholinergic: DECREASE bladder muscle contractibility [eg. antihistamines, tricyclic antidepressants (TCAs) etc]
- alpha 1 adrenergic AGONIST: CONTRACTION of prostate smooth muscles [eg. decongestants]
- Opioid Analgesics: INCREASE URINARY RETENTION
- Diuretics: INCREASE urinary frequency (manifest symptoms)
- Testosterone: STIMULATE PROSTATE GROWTH
Overview of management of BPH (MOH guidelines)
*in relation to QoL score & outflow obstruction/ complication
** ~1/2 symptomatic BPH pts will eventually require treatment
** START if symptoms bother pt OR complications occur
Considerations:
LUTS severity (IPSS)
Prostate size
Concurrent comorbidities
PSA value
Presence of irritative/ storage symptoms (long-term untreated symptoms)
Stage 1:
- NOT bothered by symptoms (QoL <1)
- outflow obstruction/ complication NOT SIGNIFICANT (Residual urine <100ml)
=> NO TREATMENT INDICATED
Stage 2:
- BOTHERED by symptoms (QoL >/=3)
- Outflow obstruction NOT SIGNIFICANT (residual urine <100ml)
=> PHARMACOTHERAPY
Stage 3:
- irrespective of symptoms
- Outflow obstruction SIGNIFICANT: uroflow >10ml/s AND residual urine >100mL
=> SURGICAL OPTION
Stage 4:
- irrespective of symptoms
- Complication: urinary retention, bladder calculi, recurrent UTI, persistent macroscopic haematuria
=> SURGERY (TransUrethral Resection of Prostate TURP)
WATCHFUL WAITING IF:
Mild symptoms (IPSS <8) OR with moderate/ severe symptoms (IPSS >/=8) who are NOT BOTHERED BY SYMPTOMS (IPSS QoL <3)
-> reassessment of symptoms using IPSS, annually or more frequent
-> lifestyle changes/ non-pharm
Non-pharmacological:
- Limit fluid intake in evening
- Minimise caffeine & alcohol intake
- Educate pts to take time to empty bladder completely & often
- Avoid medications that can exacerbate symptoms
Overview of alpha adrenergic antagonist in BPH (examples, efficacy, AE)
Types:
1. Non-selective (antagonise BOTH peripheral vascular & urinary alpha1 adrenergic receptors) eg. Doxazosin/ Terazosin
*Prazosin NOT recommended for BPH
** NEED TO TITRATE SLOWLY to therapeutic dose (RISK OF HYPOTENSION & SYNCOPE)
-> may be beneficial for hypertensive pts requiring additional BP lowering effect
**CI (BEERs list) history of syncope
* SHOULD NOT be used as monotherapy for pt with HTN & BPH
- SELECTIVE (urinary alpha1 receptors: predominant receptor in prostate & LUT) eg. Alfuzosin, Tamsulosin, Silodosin
- Lesser risk of hypotension -> dose titration NOT NECESSARY
-> for pts who don’t need aded BP lowering effect
Efficacy:
- effective in reducing LUTS ESPECIALLY in those with MODERATE/ SEVERE LUTS with SMALL prostate (<40g)
*do not reduce prostate size, don’t offer prevention for progression of BPH/ need for surgery
- NO EFFECT ON PSA
- Onset: FAST; DAYS to WEEKS
*signs & symptoms likely to recur if discontinued
S/E:
[General] Muscle weakness // Fatigue // Ejaculatory disturbance // Headache
*BEDTIME administration: decrease orthostatic effects
[NON-selective] DIZZINESS (most common) // FIRST DOSE SYNCOPE // Orthostatic hypotension
[UROSELECTIVE] LOW to NONE peripheral vascular dilation -> LESS hypotension/ syncope // EJACULATORY DISTURBANCE (delayed/retrograde ejaculation) *S>T>A
*still related with LESS SEXUAL DYSFUNCTION than 5ARI
**TAMSULOSIN: Intraoperative Floppy Iris Syndrome (IFIS)
* complicates cataract surgery
- MOA linked to blockage of alpha1 receptors in iris dilator muscle
-> planned cataract surgery: AVOID initiation UNTIL SURGERY COMPLETED // HOLD AT LEAST 14d BEFORE surgery
Overview of 5ARI in BPH (examples, MOA, efficacy, AE)
eg. Finasteride, Dutasteride
- for pts with MODERATE or SEVERE LUTS with LARGE prostate (> 40g)
- also for pts who want to avoid surgery/ cannot tolerate SE of alpha1 antagonist
MOA: inhibits 5alpha-reductase (type II) -> decrease conversion of testosterone to DHT -> REDUCE SIZE OF PROSTATE
- CAN DECREASE PSA values -> consider adding if INITIAL PSA >1.5ng/mL
^obtain PSA BEFORE INITIATION; difficult to interpret after initiation
Efficacy:
- onset SLOW; may take up to 6-12 MONTHS to decrease prostate size
SE:
- Ejaculatory disorders (reduced semen during ejaculation/ delayed ejaculation) -> HIGHER risk than alpha antagonist
- Decreased libido
- *Erectile dysfunction
- Gynecomastia, breast tenderness
- lesser risk of hypotension
CI: PREGNANT/ child-bearing age FEMALES *teratogenic
Overview of Phosphodiesterase 5 inhibitors (MOA, dose, efficacy, AE, DDI, monitoring)
Use in BPH & ED (1st line in ED)
MOA (ED): inhibit PDE-5 (involved in degradation of cGMP -> detumescence) -> enhanced cGMP activity -> induce SMOOTH MUSCLE RELAXATION -> ERECTION
**SEXUAL STIMULATION REQUIRED to cause & enhance erection
MOA for BPH unknown (some evidence to show that BPH & ED share pathophysiologic mechanism); likely smooth muscle relaxation
Dosing:
BPH: Tadalafil 5mg daily
-> MONOTHERAPY in pts with BPH-LUTS WITH or WITHOUT concurrent ED (better effect IF younger age, lower BMI, higher baseline symptoms)
*usually as ADD ON therapy, esp pts with CONCOMITANT ED
ED:
1. Sildenafil (25-100mg): 50mg PO 1h BEFORE intercourse ; onset of action 15-60mins, duration of action 4h
*take on EMPTY STOMACH; may require HEPATIC & RENAL dosage adjustments
2. Vardenafil (5-20mg): 10mg PO 1h BEFORE intercourse; onset of action 25-60mins, duration of action 4h
take on EMPTY STOMACH; may require HEPATIC dosage adjustments
3. Tadalafil (5-20mg): 5mg PO UP TO 36h BEFORE intercourse; DAILY DOSE (2.5-5mg PO daily); onset of action 15mins-2h; duration of action 36h**
^regardless of food; may required HEPATIC & RENAL dosage adjustments
4. Avanafil (50-200mg): 100mg PO 30mins BEFORE intercourse; onset of action 15-30mins; duration of action 6h
^regardless of food
*LOWER INITIAL DOSE:
- pts >/=65y/o
- concurrent alpha blocker consumption
- renal failure pts
- CYP3A4 inhibitors
Efficacy:
- DOES NOT AFFECT PROSTATE SIZE
- Onset: DAYS to WEEKS
- take WITHOUT REGARDS to timing of sexual activity *sexual stimulation needed
- ED: failure rates ~30-40% (similar among agents)
S/E: SIGNIFICANT HYPOTENSION (risk increases w use of multiple antihypertensives, concurrent ALCOHOL consumption)
- headache, rhinitis, flushing, muscle & back pain, dizziness
- prolonged erection & priapism (SEEK ED treatment if >4h)
- (very rare) sudden hearing loss; may be present with tinnitus & dizziness
- [Vardenafil] QTc prolongation
- [Tadalafil] Muscle pain (PDE11 affinity)
*OCULAR PROBLEMS (Sildenafil & Vardenafil – PDE6 in retina affinity)
- REVERSIBLE problems with color discrimination (difficulty discriminating blue from green)
- Sensitivity to light
- **Nonarteritic Anterior Ischemic Optic Neuropathy (NAION): ischemia of optic nerve due to HYPOPERFUSION by PDE5i
^risk factors: DM, smoking, HTN, CVD, dyslipidemia, >50y/o
^^pts with DECREASED VISION/ VISION LOSS: STOP use + seek IMMEDIATE MEDICAL ATTENTION
DDI:
1. NITRATES (potentially fatal hypotension)
- AVOID 12h AFTER avanafil; 24h AFTER sildenafil/vardenafil; 48h AFTER tadalafil
2. CYP3A4 inhibitors (increases serum conc of PDE5i)
Monitoring (ED):
- EFFICACY: ensure all modifiable factors addressed (dont take w food, timing & frequency of dosing, adequacy of sexual stimulation, max dose titration) -> ELSE treat with DIFFERENT PDE5i/ more invasive therapy
- SAFETY: BP // S/E // DDI // CHANGES IN CARDIAC HEALTH STATUS
Combination therapy in BPH (possible combinations)
*combination therapy provides benefits beyond monotherapy
MTOPS - finasteride + doxazosin (FD)
CombAT - Dutasteride + Tamsulosin (DT)
*ALPHA1 ANTAGONIST + 5ARI
-> long-term use: SAFE; only MILD A/E
**pts with MODERATE to SEVERE symptoms (IPSS >/=8, IPSS QoL 5-6) AND prostate size >25g: combination therapy BENEFICIAL
Initial combinations
1. alpha1 antagonist + 5ARI
*alpha1 blocker: benefit within weeks vs 5ARI: months for optimal effect
-> reserved for SYMPTOMATIC pts with ENLARGED prostate
*(SMART-1 trial) after 6mths of combination therapy: DISCONTINUATION of alpha-blocker can be considered in MODERATE BPH
- 5ARI + PDE-5i
-> beneficial to mitigate SEXUAL A/E that may arise from 5ARI/ CONCOMITANT ED
**pts with BPH & ED often have CARDIAC comorbidities: IF UNSTABLE ANGINA -> PDE-5I CONTRAINDICATED (CI concomitant use of nitrates)
DO NOT USE alpha1 antagonist + PDE5i -> potential SEVERE LIFE THREATENING HYPOTENSION
-> if used: use UROSELECTIVE alpha1 instead (alfu/ tamsu/ silod)
**MUST optimise/stabilise alpha1 antagonist BEFORE adding PDE5i
- use LOWEST EFFECTIVE PDE5i dose possible
* does not address enlargement of prostate
Pharmacological management of irritative/storage symptoms
*increased daytime urinary frequency, nocturia
Anti-muscarinics
eg. oxybutynin, tolterodine, solifenacin, trospium, darifenacin, fesoterodine
*add-on for patients who present with IRRITATIVE VOIDING symptoms (mimicking OVERACTIVE BLADDER)
MOA: blocks muscarinic receptors in detrusor muscle -> DECREASES involuntary contraction of bladder
**PVR MUST BE <250mL (150mL for more conservative guidelines
minimal risk for urinary retention
Evaluation of ED
Signs & symptoms
Sexual Health Inventory for Men (SHIM)
- Mild to NO ED: 17 - 21 pts
- Moderate to Severe: <11 pts
Workup to identify UNDERLYING CAUSE of ED
- Medical history/ Medications
- Social history
- Surgical history
- Lab results: blood glucose, lipids, testosterone etc
*CV EVALUATION
- ED may be early symptom of unidentified comorbid CVD
-> Sexual activity -> sympathetic activation may increase BP & HR -> increased risk for MI
- Low CV risk: okay
- unknown/ NOT low risk: exercise stress testing to evaluate EXERCISE CAPACITY
- UNSTABLE/ SEVERE SYMPTOMATIC CVD: DEFER (sexual activity & ED treatment) UNTIL condition STABILISED
**CARDIAC REHABILITATION + REGULAR EXERCISE USEFUL: reduces risk of CV complications with sexual activity
Overview of management of ED
- Recognise & (if possible) REVERSE/ TREAT underlying causes
- Non-pharmacological
> address modifiable risk factors: smoking, weight control, BP/glucose/lipids control, exercise, decrease alcohol
> Psychotherapy
> Devices: Vacuum Erection Devices (VEDs)
> Sugery eg. penile implant
Overview of testosterone replacement in ED (indication, SE, monitoring)
IM injection/ buccal/ patches/ topical gel/ body spray/ nasal spray/ PO
Goal: restore serum testosterone levels to normal range (300-1100ng/dL // 10.4-38.2nmol/L)
- for SYMPTOMATIC HYPOgonadism as confirmed by:
1. DECREASED libido
2. LOW serum testosterone conc
SE: Irritability, aggressive behaviour, undesirable hair growth (increased conversion of testosterone to DHT), increased BP, hepatotoxicity, dyslipidemia, polycythemia (increased risk of clots & MI/stroke), prostatic hyperplasia
*CI for prostate cancer
MONITOR serum testosterone within 1-3months AND at 6- to 12- month intervals
*DISCONTINUE if NO improvement after 3 months
Overview of Alprostadil in ED management (MOA, DDI, types, SE)
- Prostaglandin E1 analog: stimulates adenyl cyclase -> increase cAMP -> INDUCE smooth muscle RELAXATION -> ERECTION
- DO NOT REQUIRE sexual stimulation to work
- FAST onset: 5-10mins
DDI: PDE5-i
Types:
1. Intraurethral alprostadil pellet
- Duration of action: 30-60mins
*SE: pain, warmth, burning sensation in urethra, voiding difficulties, bleeding/ spotting, priapism, partners: vaginal burning/ itching
- Intracavernosal alprostadil
**preferred over intraurethral route: better efficacy
*BUT HIGHER RISK of priapism, bleeding, hematoma, fibrosis
* fear of needles, invasive, lack of spontaneity, complicated administration technique
* Titration in healthcare setting (erection for </=1h -> complete detumescence), then self-administer for NO MORE THAN 3x per week
